The regulation of brain glutamate concentration is of great importance for seizure control. Glial and neuronal uptake terminate the action of this excitatory neurotransmitter. In glia, glutamate is converted to glutamine which is returned to neurons for the resynthesis of glutamate of glutamate. Post-ictal glutamate clearance is prolonged nearly three fold in the epileptogenic human hippocampus. These findings suggest that glutamate clearance mechanisms, i.e., the glutamate-glutamine cycle, are less effective in the seizure focus. In vivo magnetic resonance spectroscopy (NMRS) studies of patients with complex partial seizures suggest mitochondrial metabolic deficiencies are associated with the seizure focus including decreased energy charge. Positron emission tomography reveals diffuse interictal hypometabolism with the maximum decreased usually centered in the epileptogenic region. Glucose oxidation is the major energy source in the mature brain used to support neuronal activity. Using in vivo and in vitro NMRS to measure the 13C label flows from glutamate to glutamine in rats and humans, we showed that the neuronal release and glial clearance of glutamate (glutamate-glutamine cycle) is a highly active metabolic pathway with a flux cost to that of glucose uptake. In rat cortex, the rate of the glutamate to glutamine cycle is in a near one to one stoichiometry with glucose oxidation and decreases with decreasing brain electrical activity. These findings suggest that both neuronal and glial energy metabolism are critical for normal glutamate release and clearance. We proposed to measure the rate of glutamate - glutamine cycling in the hippocampus and temporal neocortex of patients with medically refractory mesial temporal lobe epilepsy. Based on pilot data, we formed the following hypotheses: interictal glutamate-glutamine cycling is decreased in the epileptogenic hippocampus and temporal neocortex with interictal spiking. In the interictal state, decreased glutamate cycling reflects glial dysfunction.
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